- Email: [email protected]
Mortality of Inflammatory Bowel Disease (IBD): A Study of Data From the French National Health Insurance System in 2008
Table: IBD patients pool, medical admissions, admission/pool rates and odds ratio (95% CI)
Sa1263 Decreasing Colectomy Rates for Ulcerative Colitis Patients Following Increased Utilization of Immunomodulators and Biologics: A Population-Based Time Trend Study Gilaad G. Kaplan, Shanika De Silva, Christopher Ma, James N. Hubbard, Marie-Claude Proulx, Subrata Ghosh, Remo Panaccione Purpose: The rates of colectomy for ulcerative colitis (UC) have remained stable over time. However, with greater use of immunomodulators and the introduction of infliximab for UC, we studied whether colectomy rates for UC patients have changed. Methods: Populationbased surveillance was conducted between January 1, 1997 and December 31, 2009 to identify all adults (≥ 18 years) living in the Calgary Health Zone with a discharge abstract code for UC and a colectomy. All medical charts were reviewed to confirm the diagnosis and to record drug utilization for azathioprine /6-mercaptopurine (AZA/6-MP) and infliximab. For each year, we determined the proportion of UC patients who underwent a colectomy and were prescribed AZA/6-MP and/or infliximab. The yearly incidence of colectomy for UC was calculated by dividing the annual total number of colectomies by the annual population size for the Calgary Health Zone. Temporal changes in colectomy rates were evaluated using generalized linear regression models that assumed a Poisson distribution and adjusted for age and sex. The analysis was secondarily stratified by emergency versus elective colectomies. Results: Colectomies were performed in 455 UC patients living in the Calgary Health Zone between 1997 and 2009. Immunomodulator use ranged from 12% to 21% from 1997 to 2003, whereas after 2004 between 38% and 49% of UC patients were prescribed AZA/6-MP prior to undergoing a colectomy. From 2005 to 2009 infliximab was used between 4% and 48% of UC patients prior to undergoing a colectomy. Between 1997 and 2009 the incidence rate of colectomy for UC significantly decreased (p<0.01) from 4.2 to 3.3 per 100,000 person-years, respectively (Figure). Over the 13 year study period, the estimated annual average percent decrease in colectomy rates was -4.0% (95% CI: -2.0, -7.0; p<0.01) with the greatest decline occurring after 2004. The annual average percent decrease was predominantly observed among elective colectomy (-7.0%; 95% CI: -4.0%, -11.0%; p<0.01), whereas emergency colectomy rates did not significantly change (-1.0%; 95% CI: -5.0%, 2.0%). Conclusions: Colectomy rates in UC patients have decreased significantly since greater utilization of immunomodulators and the introduction of infliximab as a treatment option. The predominant drop in colectomy rates were observed in elective colectomies.
Sa1261 Prenatal and Birth Characteristics and Risk of Pediatric-Onset Inflammatory Bowel Disease Susan Hutfless, De-Kun Li, Melvin B. Heyman, Theodore M. Bayless, Oren Abramson, Lisa J. Herrinton BACKGROUND & AIMS: To assess the relationship between prenatal exposures and birth characteristics, and the risk of pediatric-onset IBD. METHODS: We conducted a nested case-control study of 189 cases aged ≤18 years and 3,081 age- and membership- matched controls born at a Kaiser Permanente Northern California facility between 1984 and 2006. Cases were diagnosed with IBD between 1996 and 2006. The incidence date for all cases was adjudicated by one of seven pediatric gastroenterologists trained for the purpose of the study and using a standardized chart review instrument. We obtained prenatal and birth characteristics from the electronic clinical records of the mother and child including: birth weight, gestational age, Apgar score, length of hospitalization, gravidity, parity, breast and formula feeding, cigarette smoke exposure, multiple birth, cesarean section, jaundice or hemolytic disorder, respiratory distress during birth, maternal hypertensive disorders, maternal diabetes, maternal overweight, assisted reproductive technology use, known or suspected fetal abnormality affecting management of the mother, placental or amniotic problems, maternal infection and maternal IBD. Conditional logistic regression was used to assess the associations between these factors and risk of incident IBD, Crohn's disease and ulcerative colitis. RESULTS: Maternal IBD (odds ratio [OR] 5.1, 95% confidence interval [CI] 2.0 12.9) and white race (OR 2.3, 95% CI 1.6 - 3.2) were the only factors statistically associated with pediatric-onset IBD. Maternal age <20 years (OR 2.0, 95% CI 0.8 - 4.7) and gestational hypertension (OR 1.7, 95% CI 1.0 - 2.7) were associated with pediatric-onset IBD, but did not achieve statistical significance. CONCLUSIONS: Maternal history of IBD and higher risk population group (white versus non-white) were the only characteristics, of those that we examined, that were associated with development of pediatric IBD in this well-documented population of cases and matched controls. Sa1262 Decreasing Rates of Hospital Admissions for Inflammatory Bowel Disease Between 2000 and 2009 Carlos Taxonera, Juan L. Mendoza, Dulce M. Cruz-Santamaría, Natalia López-Palacios, Cristina Alba, Norberto Mañas, María A. Tejero, María M. Cañas, Manuel Diaz-Rubio BACKGROUND & AIMS: Although few patients require hospitalization for inflammatory bowel disease (IBD), they tend to generate high resource utilization and account for most of the total costs. In addition, hospitalization negatively affects the patients' quality of life (QOL). In studies performed in Europe up to 18% of IBD patients require medical hospitalization per year. The aim of this study was to evaluate trends in the medical hospitalization rates in a cohort of IBD patients managed in a specialized IBD unit whose novel approach to management of these patients includes open access visit follow-up and a close coordination with emergency services. METHODS: The unit comprises a specialized team of health-care personnel, expert in the treatment of IBD, and caters to a catchment population of 530,000. The annual rate of medical hospitalizations for IBD respect to the registered patient pool of the unit was evaluated between 2000 and 2009. The registered patient pool included only those patients with confirmed diagnosis of IBD according to standard criteria and with at least one visit during the last 18 months. We extracted from an integrated claim database all inpatients whose hospital discharge reports included ICD-9-CM codes 555 (Crohn's disease [CD]) and 556 (ulcerative colitis [UC]) among the top three discharge diagnoses and only medical hospitalizations were recorded. Those patients whose first and second diagnoses were considered unrelated to IBD complications were excluded. Medical hospitalization rate for IBD per 100.000 habitants and disease-specific hospitalization rates were also assessed. RESULTS: The number of patients in the IBD patient pool increased from 431 patients in 2000 to 1202 in 2009, when it comprised 646 men (53.7%); 596 had UC, 570 had CD and 36 had indeterminate colitis. As shown in the table, there was a two-step reduction in admissions rate (between 2001 and 2003-2006 and between 2006 and 20072009) with significant odds ratios (relative to the year 2000 and 2003-2009*, and between 2006 [OR: 1] and 2007-2009** [OR: 0.6, 95% CI 0.4-0.9]) and significant linear trend (p<0.001). In 2009 the medical hospitalization rate for IBD was 8.9 per 100.000 habitants (5.8 per 100.000 for CD and 3 per 100.000 for UC). Hospitalization for CD accounted for two-thirds of the admissions throughout the study period. CONCLUSION: Medical hospitalization rates for IBD decreased within a 10-year period. Hospitalization rates in the last 3 years are lower than those described elsewhere. An associated reduction in the direct and indirect costs of IBD would be expected along with an improvement in the patients' QOL.
Figure: Colectomy rates from 1997 to 2009. Sa1264 Mortality of Inflammatory Bowel Disease (IBD): A Study of Data From the French National Health Insurance System in 2008 Antoine Racine, Aurelie Boutrelle, Alain Weill, Philippe Ricordeau, Marie-Christine Boutron-Ruault, Hubert Allemand, Franck Carbonnel Aim Studies performed in population-based registries suggest an increased risk of mortality in Crohn's disease (CD; SMR, 1.39 ; 1.30-1.42 ; Inflamm Bowel Dis 2010 ; 16 : 347) but not in Ulcerative Colitis (UC ; SMR 1.1 ; 0.9-1.1 ; Am J Gastroenterol 2007 ; 102 : 609). Available data come from small cohorts, with a long follow up that started long before immunosuppressive and anti-TNFα agents became widely used. Additionally, there are important geographical variations in mortality rates. The aim of this study was to assess mortality rates in CD and UC subjects in French metropolitan territory in 2008, using data from the French national health insurance (NHI). Material and Methods The study population consisted in the 48.9 million people affiliated to the general fund of the NHI which accounts for 77% of the population living in France. We selected people declared as having CD or UC, alive on December 31st, 2007. We collected the number of deaths observed in 2008 (vital status was checked from the French national institute for statistics database). The crude death rate was the ratio of the observed number of deaths over the total number of subjects declared as IBD and the age standardized mortality ratio (SMR) was estimated using
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epidemiological features and endoscopic findings in terms of CRC and high-grade (HGD), low-grade or indeterminate (LIGD) dysplasia were recorded. Results: 831 patients (34% leftsided, 56% extensive UC) were included. Median follow-up from UC diagnosis was 19±9 years. Among known risk factors for CRC: primary sclerosing cholangitis (PSC) 3% and familial history of CRC 7%. 90% of patients took oral mesalazine at any time during UC course. In all, 1,866 colonoscopies were performed (median per patient=1, IQR=1-3). Median time from UC diagnosis to first colonoscopy was 11 years (IQR=8-16) for extensive UC and 13 years (IQR=10-18) for left-sided UC. Twenty-six cases of CRC were found (median time from UC diagnosis to CRC diagnosis=11.5 years, IQR=4.7-20.2), 27% of them within the first 8 years from UC diagnosis. One-hundred and sixt One-hundred and sixty patients y patients had 262 dysplasias (26 HGD and 234 LIGD). The cumulative probability of developing HGD/CRC was 1.2 %, 2%, 4.8% and 11.1% at 5, 10, 20, and 30 years of disease, respectively. PSC and male gender were independent predictors for the development of HGD/CRC ([RR13.5, IC95% 4.3-42; p<0.017] and [RR2.9, IC95% 1.2-7; p<0.001], respectively). The use of immunomodulators and being included in a colonoscopy surveillance program were independent protective factors ([RR0.23, IC95% 0.08-0.64; p=0.005] and [RR0.33, IC95% 0.15-0.72; p=0.005], respectively). Conclusion: HGD/CRC incidence in Spain seems to be lower than previously reported in other areas and this risk seems to exist since UC diagnosis. Prospective, population-based studies are warranted in order to optimise colonoscopy surveillance programs.
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age-specific all cause mortality rates in the affiliated population. Results In 2008, we registered 49331 CD cases (29173 women) and 39523 UC cases (19946 women). Median ages were 44 years for both sexes in CD, 49 years in UC women and 51 years in UC men. During the study period, 327 patients with CD and 315 patients with UC died. The crude death rate was 66.3 /10,000 for CD and 79.0/10,000 for UC. SMRs for CD were 1.27 (95% CI 1.1-1.4) in both sexes, 1.48 (95%CI 1.3-1.7) in women and 1.08 (95%CI 0.9-1.3) in men. In women, higher SMRs were observed between 20 and 59 years. In UC, the SMR was identical in men 0.89 (0.8-1.0) and women 0.97 (0.8-1.2) Conclusion In France, in 2008, we found that women with CD had a significantly increased risk of death as compared to the control affiliated population. Analysis of causes of death and of specific medications will provide important information to assess the real impact of novel therapies in this population. Sa1265 Detection of Campylobacter Concisus in Colonic Biopsies From Adult Patients With Ulcerative Colitis Indrani Mukhopadhya, John M. Thomson, Richard Hansen, Susan H. Berry, Emad ElOmar, Georgina L. Hold Introduction: The critical role of luminal bacteria in the pathogenesis of ulcerative colitis (UC) is well recognized, but an individual causative microorganism has not been singled out so far. Campylobacter concisus and other non-jejuni species of Campylobacter have been implicated as putative aetiological agents of inflammatory bowel disease in children. The prevalence of these bacteria in adult patients with IBD would give a better insight into their role as immune triggers that initiate and perpetuate chronic inflammation. This study investigated the prevalence of Campylobacter concisus in colonic biopsy samples from adult patients with UC and compared that with control patients. Methods: Adult patients who were undergoing diagnostic colonoscopy were recruited for the study, which included 68 patients with histologically proven UC and 79 control patients with no macroscopic or microscopic evidence of IBD. Biopsies were obtained during colonoscopy and immediately snap frozen in liquid nitrogen and transferred to a -80°C freezer. DNA was extracted from the biopsy samples and subjected to polymerase chain reaction utilising Campylobacter genusspecific primers. Positive Campylobacter samples were then subjected to nested PCR using Campylobacter concisus-specific primers. Fisher's exact test was used to examine any statistical difference in the presence of Campylobacter and Campylobacter concisus between the study groups. Results: Detection of all Campylobacter utilising genus specific primers was significantly higher in cases of UC, with a prevalence of 72.1% (49/68) compared to 24.1% (19/ 79) in control patients (p= 0.0001). Nested PCR for Campylobacter concisus was positive in 30.9% (21/68) of biopsy samples from patients with UC, which was significantly higher than the prevalence rate of 7.6% (6/79) from control patients (p= 0.0005). Conclusion: The higher prevalence of Campylobacter and more specifically Campylobacter concisus in biopsy samples from adult patients with UC suggest a key role of this genus of bacteria in initiating the chronic inflammation that is characteristically seen in UC. To the best of our knowledge this is the first report of this association of Campylobacter concisus with UC in adult patients.
Figure 1. A receiver-operator characteristic (ROC) curve showing the relative performace of three classification algorithms. NOD2, in green, attempts to classify known UC and CD patients using 3 independent NOD2 loci alone. Smoke, in blue, uses a history of smoking as the sole predictor. The full model, in red, uses all known IBD loci, including NOD2, as well as smoking history. The legend, in the bottom right corner reports the AUC, or area under the ROC curve, for each of these models. Sa1267 Increased Frequency of Risk Alleles in a Cohort of Healthy First Degree Relatives of Crohn's Disease Patients - A Report From the Michael J. Howorth/ CCFC GEM Project Mark S. Silverberg, Wei Xu, Andrew D. Paterson, Ken Croitoru Introduction: The etiology of Crohn's disease (CD) is related to a dysregulated immune response to the host microbiome in a genetically susceptible individual. Numerous genetic associations have been identified for CD but it is as yet unclear how these factors lead to chronic intestinal inflammation. The CCFC GEM Project is a study of healthy siblings and offspring (FDRs) of patients with CD designed to identify the genetic, environmental, and microbial factors that lead to the onset of CD. This is the first report describing the prevalence of genetic risk factors for CD in a population of healthy FDRs. Methods: Healthy FDRs (aged 6-35 years) of CD-affected individuals recruited from across Canada as part of the CCFC GEM Project provided, demographic information, and medical, family, environmental and dietary histories. Subjects with GI symptoms or other clinical evidence suggestive of IBD or IBS were excluded. Biospecimens obtained included blood, stool and urine samples. Genomic DNA was extracted from whole blood. 15 SNPs with known associations with CD were genotyped using Sequenom and TaqMan platforms. The allele frequencies in the FDRs (n=732) was compared to cohorts with CD (n=870), ulcerative colitis (UC) (n=725) and healthy controls (HC) (n=982). A multiple SNP risk score, defined as a weighted summary of risk alleles from the 15 CD-related SNPs was calculated. The weights assigned to each risk allele were based on the estimated effect size (Odds Ratio (OR)) from published literature. The analysis was restricted to those subjects identified as Caucasians only. T-tests were applied to compare the risk scores between groups. Results: The mean risk score (MRS) and standard deviation (SD) for each group for the 15 CD-related SNPs is shown in Table 1. The MRS of FDRs was significantly higher than that of HC and UC, but not higher than that of CD. Pearson Chi sq tests were used to compare the frequency of homozygosity and compound heterozygosity of three NOD2 SNPs (rs2066844, rs2066845, rs2066847). The p values for pair-wise comparisons of FDRs, CD and UC with HC were 1.4E-6, 4.2E-21 and 0.16, respectively. FDRs were demonstrated to have a significantly higher frequency of CD risk alleles at NOD2 compared to HC (Table 2). Conclusions: These data demonstrate that this cohort of healthy FDRs is enriched for CD-associated risk alleles and is an ideal study population for evaluating the gene-environment interactions in a prospective fashion and to eventually identify the specific etiology of CD. Funding : CCFC/Michael J.Howorth GEM Project and the NIH/NIDDK. Table 1. Mean risk scores of each cohort, and their differences with that of FDRs.
Sa1266 The Utility of Genetics in Classifying Ulcerative Colitis and Crohn's Disease Patients Jonah B. Essers, Elisabeth B. Cole, Marla Dubinsky, Talin Haritunians, Joshua R. Korzenik, Dermot P. McGovern, Bruce E. Sands, Stephan R. Targan, Kent D. Taylor, Nick Teleten, Ramnik J. Xavier, Mark J. Daly, Jerome I. Rotter, Mark S. Silverberg The heterogeneous presentation of inflammatory bowel disease (IBD) poses a major diagnostic challenge to clinicians. Although clinical parameters and mainstream biomarkers have some role in classifying IBD patients into relevant subgroups, their utility is suboptimal. Despite reported associations between DNA variants and IBD phenotypes, genotyping patients has not been adopted as a mainstream risk stratification strategy because the accuracy of these genetic models are not yet compelling. With the recent report of 100 distinct genetic loci convincingly associated with IBD, we felt it timely to comprehensively assess the contribution of risk alleles in phenotype classification1-3. Recognizing that the most robust risk stratification schemes will likely combine several types of predictors (e.g. smoking, serologies, genetics), we have developed a novel classification strategy that leverages the cumulative burden of genetic risk in IBD in over 2200 well-phenotyped Crohn's disease (CD) and ulcerative colitis (UC) patients. We employ machine learning algorithms, which have been widely successful in employing genetic data, to sub-classify important disease phenotypes. Two strategies have increased the discriminatory power of our approach over previously reported genetic risk models: (1) Instead of considering individual genetic variants' contribution to disease behavior, we use a joint risk statistic that describes all known CD-specific or UC-specific risk; (2) We combine genotypic, serologic, and clinical predictors into a comprehensive risk model. To demonstrate the power of this approach, we will specifically highlight the challenge of clinically distinguishing ulcerative colitis(UC) from Crohn's disease(CD), which can be difficult in 10% of patients with colon-only disease in spite of mainstream diagnostic tools. We assessed the value of all 100 risk alleles in aggregate and show additive value of combining smoking status and genetic risk in accurately classifying these patients (figure 1). We therefore believe that genotype data is poised to be an important addition to a classification strategy in conjunction with other known predictors. The development of tools that convincingly stratify patients into clinically relevant subgroups will allow earlier and more appropriate tailoring of therapy for IBD patients. 1. Barrett, J.C., Hansoul, S., Nicolae, D.L., et al. Genomewide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40, 955-62 (2008). 2. Franke, A., McGovern, D.P., Barrett, J.C., et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet (2010). 3. McGovern, D.P., Gardet, A., Torkvist, L., et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42, 332-7 (2010).
Table 2. Individuals with one or more NOD2 risk alleles vs. no risk alleles in HC, FDR, CD, and UC cohorts.
* OR, CI and p values are calculated for each Cohort vs HC
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Sa1263 Decreasing Colectomy Rates for Ulcerative Colitis Patients Following Increased Utilization of Immunomodulators and Biologics: A Population-Based Time Trend Study Gilaad G. Kaplan, Shanika De Silva, Christopher Ma, James N. Hubbard, Marie-Claude Proulx, Subrata Ghosh, Remo Panaccione Purpose: The rates of colectomy for ulcerative colitis (UC) have remained stable over time. However, with greater use of immunomodulators and the introduction of infliximab for UC, we studied whether colectomy rates for UC patients have changed. Methods: Populationbased surveillance was conducted between January 1, 1997 and December 31, 2009 to identify all adults (≥ 18 years) living in the Calgary Health Zone with a discharge abstract code for UC and a colectomy. All medical charts were reviewed to confirm the diagnosis and to record drug utilization for azathioprine /6-mercaptopurine (AZA/6-MP) and infliximab. For each year, we determined the proportion of UC patients who underwent a colectomy and were prescribed AZA/6-MP and/or infliximab. The yearly incidence of colectomy for UC was calculated by dividing the annual total number of colectomies by the annual population size for the Calgary Health Zone. Temporal changes in colectomy rates were evaluated using generalized linear regression models that assumed a Poisson distribution and adjusted for age and sex. The analysis was secondarily stratified by emergency versus elective colectomies. Results: Colectomies were performed in 455 UC patients living in the Calgary Health Zone between 1997 and 2009. Immunomodulator use ranged from 12% to 21% from 1997 to 2003, whereas after 2004 between 38% and 49% of UC patients were prescribed AZA/6-MP prior to undergoing a colectomy. From 2005 to 2009 infliximab was used between 4% and 48% of UC patients prior to undergoing a colectomy. Between 1997 and 2009 the incidence rate of colectomy for UC significantly decreased (p<0.01) from 4.2 to 3.3 per 100,000 person-years, respectively (Figure). Over the 13 year study period, the estimated annual average percent decrease in colectomy rates was -4.0% (95% CI: -2.0, -7.0; p<0.01) with the greatest decline occurring after 2004. The annual average percent decrease was predominantly observed among elective colectomy (-7.0%; 95% CI: -4.0%, -11.0%; p<0.01), whereas emergency colectomy rates did not significantly change (-1.0%; 95% CI: -5.0%, 2.0%). Conclusions: Colectomy rates in UC patients have decreased significantly since greater utilization of immunomodulators and the introduction of infliximab as a treatment option. The predominant drop in colectomy rates were observed in elective colectomies.
Sa1261 Prenatal and Birth Characteristics and Risk of Pediatric-Onset Inflammatory Bowel Disease Susan Hutfless, De-Kun Li, Melvin B. Heyman, Theodore M. Bayless, Oren Abramson, Lisa J. Herrinton BACKGROUND & AIMS: To assess the relationship between prenatal exposures and birth characteristics, and the risk of pediatric-onset IBD. METHODS: We conducted a nested case-control study of 189 cases aged ≤18 years and 3,081 age- and membership- matched controls born at a Kaiser Permanente Northern California facility between 1984 and 2006. Cases were diagnosed with IBD between 1996 and 2006. The incidence date for all cases was adjudicated by one of seven pediatric gastroenterologists trained for the purpose of the study and using a standardized chart review instrument. We obtained prenatal and birth characteristics from the electronic clinical records of the mother and child including: birth weight, gestational age, Apgar score, length of hospitalization, gravidity, parity, breast and formula feeding, cigarette smoke exposure, multiple birth, cesarean section, jaundice or hemolytic disorder, respiratory distress during birth, maternal hypertensive disorders, maternal diabetes, maternal overweight, assisted reproductive technology use, known or suspected fetal abnormality affecting management of the mother, placental or amniotic problems, maternal infection and maternal IBD. Conditional logistic regression was used to assess the associations between these factors and risk of incident IBD, Crohn's disease and ulcerative colitis. RESULTS: Maternal IBD (odds ratio [OR] 5.1, 95% confidence interval [CI] 2.0 12.9) and white race (OR 2.3, 95% CI 1.6 - 3.2) were the only factors statistically associated with pediatric-onset IBD. Maternal age <20 years (OR 2.0, 95% CI 0.8 - 4.7) and gestational hypertension (OR 1.7, 95% CI 1.0 - 2.7) were associated with pediatric-onset IBD, but did not achieve statistical significance. CONCLUSIONS: Maternal history of IBD and higher risk population group (white versus non-white) were the only characteristics, of those that we examined, that were associated with development of pediatric IBD in this well-documented population of cases and matched controls. Sa1262 Decreasing Rates of Hospital Admissions for Inflammatory Bowel Disease Between 2000 and 2009 Carlos Taxonera, Juan L. Mendoza, Dulce M. Cruz-Santamaría, Natalia López-Palacios, Cristina Alba, Norberto Mañas, María A. Tejero, María M. Cañas, Manuel Diaz-Rubio BACKGROUND & AIMS: Although few patients require hospitalization for inflammatory bowel disease (IBD), they tend to generate high resource utilization and account for most of the total costs. In addition, hospitalization negatively affects the patients' quality of life (QOL). In studies performed in Europe up to 18% of IBD patients require medical hospitalization per year. The aim of this study was to evaluate trends in the medical hospitalization rates in a cohort of IBD patients managed in a specialized IBD unit whose novel approach to management of these patients includes open access visit follow-up and a close coordination with emergency services. METHODS: The unit comprises a specialized team of health-care personnel, expert in the treatment of IBD, and caters to a catchment population of 530,000. The annual rate of medical hospitalizations for IBD respect to the registered patient pool of the unit was evaluated between 2000 and 2009. The registered patient pool included only those patients with confirmed diagnosis of IBD according to standard criteria and with at least one visit during the last 18 months. We extracted from an integrated claim database all inpatients whose hospital discharge reports included ICD-9-CM codes 555 (Crohn's disease [CD]) and 556 (ulcerative colitis [UC]) among the top three discharge diagnoses and only medical hospitalizations were recorded. Those patients whose first and second diagnoses were considered unrelated to IBD complications were excluded. Medical hospitalization rate for IBD per 100.000 habitants and disease-specific hospitalization rates were also assessed. RESULTS: The number of patients in the IBD patient pool increased from 431 patients in 2000 to 1202 in 2009, when it comprised 646 men (53.7%); 596 had UC, 570 had CD and 36 had indeterminate colitis. As shown in the table, there was a two-step reduction in admissions rate (between 2001 and 2003-2006 and between 2006 and 20072009) with significant odds ratios (relative to the year 2000 and 2003-2009*, and between 2006 [OR: 1] and 2007-2009** [OR: 0.6, 95% CI 0.4-0.9]) and significant linear trend (p<0.001). In 2009 the medical hospitalization rate for IBD was 8.9 per 100.000 habitants (5.8 per 100.000 for CD and 3 per 100.000 for UC). Hospitalization for CD accounted for two-thirds of the admissions throughout the study period. CONCLUSION: Medical hospitalization rates for IBD decreased within a 10-year period. Hospitalization rates in the last 3 years are lower than those described elsewhere. An associated reduction in the direct and indirect costs of IBD would be expected along with an improvement in the patients' QOL.
Figure: Colectomy rates from 1997 to 2009. Sa1264 Mortality of Inflammatory Bowel Disease (IBD): A Study of Data From the French National Health Insurance System in 2008 Antoine Racine, Aurelie Boutrelle, Alain Weill, Philippe Ricordeau, Marie-Christine Boutron-Ruault, Hubert Allemand, Franck Carbonnel Aim Studies performed in population-based registries suggest an increased risk of mortality in Crohn's disease (CD; SMR, 1.39 ; 1.30-1.42 ; Inflamm Bowel Dis 2010 ; 16 : 347) but not in Ulcerative Colitis (UC ; SMR 1.1 ; 0.9-1.1 ; Am J Gastroenterol 2007 ; 102 : 609). Available data come from small cohorts, with a long follow up that started long before immunosuppressive and anti-TNFα agents became widely used. Additionally, there are important geographical variations in mortality rates. The aim of this study was to assess mortality rates in CD and UC subjects in French metropolitan territory in 2008, using data from the French national health insurance (NHI). Material and Methods The study population consisted in the 48.9 million people affiliated to the general fund of the NHI which accounts for 77% of the population living in France. We selected people declared as having CD or UC, alive on December 31st, 2007. We collected the number of deaths observed in 2008 (vital status was checked from the French national institute for statistics database). The crude death rate was the ratio of the observed number of deaths over the total number of subjects declared as IBD and the age standardized mortality ratio (SMR) was estimated using
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epidemiological features and endoscopic findings in terms of CRC and high-grade (HGD), low-grade or indeterminate (LIGD) dysplasia were recorded. Results: 831 patients (34% leftsided, 56% extensive UC) were included. Median follow-up from UC diagnosis was 19±9 years. Among known risk factors for CRC: primary sclerosing cholangitis (PSC) 3% and familial history of CRC 7%. 90% of patients took oral mesalazine at any time during UC course. In all, 1,866 colonoscopies were performed (median per patient=1, IQR=1-3). Median time from UC diagnosis to first colonoscopy was 11 years (IQR=8-16) for extensive UC and 13 years (IQR=10-18) for left-sided UC. Twenty-six cases of CRC were found (median time from UC diagnosis to CRC diagnosis=11.5 years, IQR=4.7-20.2), 27% of them within the first 8 years from UC diagnosis. One-hundred and sixt One-hundred and sixty patients y patients had 262 dysplasias (26 HGD and 234 LIGD). The cumulative probability of developing HGD/CRC was 1.2 %, 2%, 4.8% and 11.1% at 5, 10, 20, and 30 years of disease, respectively. PSC and male gender were independent predictors for the development of HGD/CRC ([RR13.5, IC95% 4.3-42; p<0.017] and [RR2.9, IC95% 1.2-7; p<0.001], respectively). The use of immunomodulators and being included in a colonoscopy surveillance program were independent protective factors ([RR0.23, IC95% 0.08-0.64; p=0.005] and [RR0.33, IC95% 0.15-0.72; p=0.005], respectively). Conclusion: HGD/CRC incidence in Spain seems to be lower than previously reported in other areas and this risk seems to exist since UC diagnosis. Prospective, population-based studies are warranted in order to optimise colonoscopy surveillance programs.
AGA Abstracts
age-specific all cause mortality rates in the affiliated population. Results In 2008, we registered 49331 CD cases (29173 women) and 39523 UC cases (19946 women). Median ages were 44 years for both sexes in CD, 49 years in UC women and 51 years in UC men. During the study period, 327 patients with CD and 315 patients with UC died. The crude death rate was 66.3 /10,000 for CD and 79.0/10,000 for UC. SMRs for CD were 1.27 (95% CI 1.1-1.4) in both sexes, 1.48 (95%CI 1.3-1.7) in women and 1.08 (95%CI 0.9-1.3) in men. In women, higher SMRs were observed between 20 and 59 years. In UC, the SMR was identical in men 0.89 (0.8-1.0) and women 0.97 (0.8-1.2) Conclusion In France, in 2008, we found that women with CD had a significantly increased risk of death as compared to the control affiliated population. Analysis of causes of death and of specific medications will provide important information to assess the real impact of novel therapies in this population. Sa1265 Detection of Campylobacter Concisus in Colonic Biopsies From Adult Patients With Ulcerative Colitis Indrani Mukhopadhya, John M. Thomson, Richard Hansen, Susan H. Berry, Emad ElOmar, Georgina L. Hold Introduction: The critical role of luminal bacteria in the pathogenesis of ulcerative colitis (UC) is well recognized, but an individual causative microorganism has not been singled out so far. Campylobacter concisus and other non-jejuni species of Campylobacter have been implicated as putative aetiological agents of inflammatory bowel disease in children. The prevalence of these bacteria in adult patients with IBD would give a better insight into their role as immune triggers that initiate and perpetuate chronic inflammation. This study investigated the prevalence of Campylobacter concisus in colonic biopsy samples from adult patients with UC and compared that with control patients. Methods: Adult patients who were undergoing diagnostic colonoscopy were recruited for the study, which included 68 patients with histologically proven UC and 79 control patients with no macroscopic or microscopic evidence of IBD. Biopsies were obtained during colonoscopy and immediately snap frozen in liquid nitrogen and transferred to a -80°C freezer. DNA was extracted from the biopsy samples and subjected to polymerase chain reaction utilising Campylobacter genusspecific primers. Positive Campylobacter samples were then subjected to nested PCR using Campylobacter concisus-specific primers. Fisher's exact test was used to examine any statistical difference in the presence of Campylobacter and Campylobacter concisus between the study groups. Results: Detection of all Campylobacter utilising genus specific primers was significantly higher in cases of UC, with a prevalence of 72.1% (49/68) compared to 24.1% (19/ 79) in control patients (p= 0.0001). Nested PCR for Campylobacter concisus was positive in 30.9% (21/68) of biopsy samples from patients with UC, which was significantly higher than the prevalence rate of 7.6% (6/79) from control patients (p= 0.0005). Conclusion: The higher prevalence of Campylobacter and more specifically Campylobacter concisus in biopsy samples from adult patients with UC suggest a key role of this genus of bacteria in initiating the chronic inflammation that is characteristically seen in UC. To the best of our knowledge this is the first report of this association of Campylobacter concisus with UC in adult patients.
Figure 1. A receiver-operator characteristic (ROC) curve showing the relative performace of three classification algorithms. NOD2, in green, attempts to classify known UC and CD patients using 3 independent NOD2 loci alone. Smoke, in blue, uses a history of smoking as the sole predictor. The full model, in red, uses all known IBD loci, including NOD2, as well as smoking history. The legend, in the bottom right corner reports the AUC, or area under the ROC curve, for each of these models. Sa1267 Increased Frequency of Risk Alleles in a Cohort of Healthy First Degree Relatives of Crohn's Disease Patients - A Report From the Michael J. Howorth/ CCFC GEM Project Mark S. Silverberg, Wei Xu, Andrew D. Paterson, Ken Croitoru Introduction: The etiology of Crohn's disease (CD) is related to a dysregulated immune response to the host microbiome in a genetically susceptible individual. Numerous genetic associations have been identified for CD but it is as yet unclear how these factors lead to chronic intestinal inflammation. The CCFC GEM Project is a study of healthy siblings and offspring (FDRs) of patients with CD designed to identify the genetic, environmental, and microbial factors that lead to the onset of CD. This is the first report describing the prevalence of genetic risk factors for CD in a population of healthy FDRs. Methods: Healthy FDRs (aged 6-35 years) of CD-affected individuals recruited from across Canada as part of the CCFC GEM Project provided, demographic information, and medical, family, environmental and dietary histories. Subjects with GI symptoms or other clinical evidence suggestive of IBD or IBS were excluded. Biospecimens obtained included blood, stool and urine samples. Genomic DNA was extracted from whole blood. 15 SNPs with known associations with CD were genotyped using Sequenom and TaqMan platforms. The allele frequencies in the FDRs (n=732) was compared to cohorts with CD (n=870), ulcerative colitis (UC) (n=725) and healthy controls (HC) (n=982). A multiple SNP risk score, defined as a weighted summary of risk alleles from the 15 CD-related SNPs was calculated. The weights assigned to each risk allele were based on the estimated effect size (Odds Ratio (OR)) from published literature. The analysis was restricted to those subjects identified as Caucasians only. T-tests were applied to compare the risk scores between groups. Results: The mean risk score (MRS) and standard deviation (SD) for each group for the 15 CD-related SNPs is shown in Table 1. The MRS of FDRs was significantly higher than that of HC and UC, but not higher than that of CD. Pearson Chi sq tests were used to compare the frequency of homozygosity and compound heterozygosity of three NOD2 SNPs (rs2066844, rs2066845, rs2066847). The p values for pair-wise comparisons of FDRs, CD and UC with HC were 1.4E-6, 4.2E-21 and 0.16, respectively. FDRs were demonstrated to have a significantly higher frequency of CD risk alleles at NOD2 compared to HC (Table 2). Conclusions: These data demonstrate that this cohort of healthy FDRs is enriched for CD-associated risk alleles and is an ideal study population for evaluating the gene-environment interactions in a prospective fashion and to eventually identify the specific etiology of CD. Funding : CCFC/Michael J.Howorth GEM Project and the NIH/NIDDK. Table 1. Mean risk scores of each cohort, and their differences with that of FDRs.
Sa1266 The Utility of Genetics in Classifying Ulcerative Colitis and Crohn's Disease Patients Jonah B. Essers, Elisabeth B. Cole, Marla Dubinsky, Talin Haritunians, Joshua R. Korzenik, Dermot P. McGovern, Bruce E. Sands, Stephan R. Targan, Kent D. Taylor, Nick Teleten, Ramnik J. Xavier, Mark J. Daly, Jerome I. Rotter, Mark S. Silverberg The heterogeneous presentation of inflammatory bowel disease (IBD) poses a major diagnostic challenge to clinicians. Although clinical parameters and mainstream biomarkers have some role in classifying IBD patients into relevant subgroups, their utility is suboptimal. Despite reported associations between DNA variants and IBD phenotypes, genotyping patients has not been adopted as a mainstream risk stratification strategy because the accuracy of these genetic models are not yet compelling. With the recent report of 100 distinct genetic loci convincingly associated with IBD, we felt it timely to comprehensively assess the contribution of risk alleles in phenotype classification1-3. Recognizing that the most robust risk stratification schemes will likely combine several types of predictors (e.g. smoking, serologies, genetics), we have developed a novel classification strategy that leverages the cumulative burden of genetic risk in IBD in over 2200 well-phenotyped Crohn's disease (CD) and ulcerative colitis (UC) patients. We employ machine learning algorithms, which have been widely successful in employing genetic data, to sub-classify important disease phenotypes. Two strategies have increased the discriminatory power of our approach over previously reported genetic risk models: (1) Instead of considering individual genetic variants' contribution to disease behavior, we use a joint risk statistic that describes all known CD-specific or UC-specific risk; (2) We combine genotypic, serologic, and clinical predictors into a comprehensive risk model. To demonstrate the power of this approach, we will specifically highlight the challenge of clinically distinguishing ulcerative colitis(UC) from Crohn's disease(CD), which can be difficult in 10% of patients with colon-only disease in spite of mainstream diagnostic tools. We assessed the value of all 100 risk alleles in aggregate and show additive value of combining smoking status and genetic risk in accurately classifying these patients (figure 1). We therefore believe that genotype data is poised to be an important addition to a classification strategy in conjunction with other known predictors. The development of tools that convincingly stratify patients into clinically relevant subgroups will allow earlier and more appropriate tailoring of therapy for IBD patients. 1. Barrett, J.C., Hansoul, S., Nicolae, D.L., et al. Genomewide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40, 955-62 (2008). 2. Franke, A., McGovern, D.P., Barrett, J.C., et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet (2010). 3. McGovern, D.P., Gardet, A., Torkvist, L., et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42, 332-7 (2010).
Table 2. Individuals with one or more NOD2 risk alleles vs. no risk alleles in HC, FDR, CD, and UC cohorts.
* OR, CI and p values are calculated for each Cohort vs HC
AGA Abstracts
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